Mechanisms underlying Alzheimer's disease (AD) has progressed based on the 'amyloid cascade hypothesis', which posits that A[unreadable] deposits primarily contribute to neuronal death and neurofibrillary tangle (NFT) formation. Animal modeling studies support the idea that A[unreadable] can trigger NFT formation. Therefore, current AD therapy driven by the amyloid hypothesis mostly focuses on reducing cerebral A[unreadable] levels. However, recent studies showed that A[unreadable]40 had anti-amyloidogenic effect in vivo thereby suggesting that amyloid therapy targeting A[unreadable] without any selectivity of single A[unreadable] species should be approached with caution. We hypothesize that A[unreadable]40 can attenuate memory impairment and may therefore represent a protective species of A[unreadable]. To address this hypothesis, we will test the effect of secreted A[unreadable] on the cognitive function in the rTg4510 mouse model which develops NFTs, neuronal loss and memory impairment in an age-dependent manner. The rTg4510 mice have several advantages such as rapid progression of tau pathology, strong tau expression in a forebrain-specific pattern, and conditional expression of tau. To determine the impact of A[unreadable]40 in the mouse brain, we will drive A[unreadable] production using the method of brain-wide transduction of neurons by administering adeno-associated virus (AAV) intracerebroventricularly (i.c.v.) to newborn pups. An AAV construct expressing A[unreadable]40 or A[unreadable]42 peptide fused to the C-terminal end of the BRI protein will be utilized so that we can focus our studies specifically on the A[unreadable]40 or A[unreadable]42 peptides. This method will allow us to avoid confounding, albeit potentially interesting, effects arising from APP processing derivatives and the subcellular localization of processing. The rTg4510 mice with or without A[unreadable] peptide expression will be analyzed for cognitive function, brain biochemistry, and neuropathology. If our hypothesis is proven correct, the strategies of selective increases in A[unreadable]40 levels may be effective at reducing the risk for development of AD. In any case, the results will provide important clues to answer whether A[unreadable] peptides act to deteriorate cognitive function. PUBLIC HEALTH RELEVANCE: During the last 20 years, our understanding of mechanisms underlying Alzheimer's disease, a progressive neurological disorder with memory loss and confusion, has progressed based on the amyloid hypothesis. Recent study showed that A[unreadable]40 may have an anti-amyloidogenic effect in vivo suggesting that amyloid therapy targeting A[unreadable] without any selectivity of specific A[unreadable] species should be approached with caution. Here, we hypothesize that A[unreadable]40 may attenuate memory impairment and the strategies of selectively increasing A[unreadable]40 levels may be effective at reducing the risk for development of AD.